The control of vascular permeability is essential for maintenance of normovolemia, most importantly in constrained spaces of the body such as the eye and the brain. Vasogenic cerebral edema arises from transvascular leakage caused by mechanical failure or dysfunction of the endothelial tight junctions of the blood-brain barrier (BBB), and is characterized by an increase in extracellular fluid volume due to the increased permeability of brain capillary endothelial cells to macromolecular serum proteins (e.g., albumin). Under normal physiological conditions, the entry of plasma protein-containing fluid into the extracellular space is limited by endothelial cell tight junctions. However, in the presence of massive injury there is increased permeability of brain capillary endothelial cells. Vasogenic edema can displace the brain hemisphere; severe edema can lead to cerebral herniation and contribute to neuronal cell death. Vasogenic edema is often associated with subdural hemorrhage (e.g., from a cranial injury) and hemorrhagic stroke.
Diabetic retinopathy (DR) is the leading cause of vision loss in working adults (Klein et al., Opthalmology 105:1801-1815 (1998); Ciulla et al., Diabetes Care 26:2653-2664 (2003)). Although its incidence and progression can be reduced by intensive glycemic and blood pressure control (The Diabetes Control and Complications Trial Research Group, N. Engl. J. Med. 329:977-986 (1993); Stratton et al., BMJ 321:405-412 (2000); UK Prospective Diabetes Study Group BMJ. 317:703-713 (1998) [published erratum appears in BMJ 1999 Jan. 2; 318(7175):29]), nearly all patients with type 1 diabetes mellitus (DM) and over 60% of those with type 2 DM develop retinal microvascular abnormalities termed nonproliferative diabetic retinopathy (NPDR), and 20% to 30% of these patients advance to active proliferative diabetic retinopathy (PDR) and/or diabetic macular edema (DME) (Aiello et al., Diabetes Care 21:143-156 (1998); Klein et al., Opthalmology 91:1464-1474 (1984); Javitt et al. Diabetes Care 17:909-917 (1994); Williams et al., Eye 18:963-983 (2004)). While photocoagulation surgery and vitrectomy are highly effective in reducing vision loss, preventative treatments for PDR and DME remain a major unmet clinical need.
Increased retinal vascular permeability (RVP) is a primary cause of DME and a characteristic finding in PDR, as well as other disorders. The retinal vascular barrier has an essential role in maintaining the composition of both of retinal interstitial fluid and the vitreous humor. An increase in RVP occurs in early diabetes and the magnitude of RVP correlates with the severity of DR (Krogsaa et al., Acta Opthalmol. (Copenh.) 59:689-694 (1981); Plehwe et al., Br. J. Opthalmol. 73:255-260 (1989); Lattanzio et al., Eur. J. Opthalmol. 12:482-487 (2002)). Although the etiology of DME is not fully understood, a primary cause of macular thickening appears to involve the diffusion of proteins and lipids across the retinal endothelium into the retina resulting in fluid retention and lipid exudates within the macula (Knudsen et al., Diabetes Care 25:2328-2334 (2002)). Over the past decade, a number of groups have demonstrated that growth factors and hormones, including vascular endothelial growth factor (VEGF), angiotensin II, and interleukin-6, are elevated in the vitreous of individuals with PDR and DME (Aiello et al., N. Engl. J. Med. 331:1480-1487 (1994); Funatsu et al., Opthalmology 110:1690-1696 (2003); Funatsu et al., Am. J. Opthalmol. 133:537-543 (2002); Simo et al., Diabetes Care 27:287-288 (2004); Simo et al., Clin. Sci. (Lond.) 104:223-230 (2003); Adamis et al., Am. J. Opthalmol. 118:445-450 (1994); Miller et al., Am. J. Pathol. 145:574-584 (1994)). The vitreous also contains anti-angiogenic and anti-permeability factors, such as pigment epithelium-derived factor (PEDF) and angiostatin, which can oppose the effects of VEGF (King et al., N. Engl. J. Med. 342:349-351 (2000); Ogata et al., Am. J. Opthalmol. 134:348-353 (2002); Raisler et al., Proc. Natl. Acad. Sci. U.S.A. 99:8909-8914 (2002); Dawson et al., Science 285:245-248 (1999); Spranger et al., Diabetologia 43:1404-1407 (2000)). These reports support the general proposition that vitreous fluid contains proteins that correlate with specific retinal pathologies, and that proteins in the vitreous compartment affect retinal vascular functions. A variety of retinal vascular conditions are believed to be associated with increased permeability; many of these conditions, e.g., the ischemic retinopathies, are thought to be mediated by these and other as yet unknown factors.